Oral health in patients scheduled for hematopoietic stem cell transplantation in the Orastem study

Despite advances in transplant medicine, prevalence of complications after hematopoietic stem cell transplantation (HSCT) remains high. The impact of pre-HSCT oral health factors on the incidence and severity of complications post-HSCT is poorly understood. The aim of this prospective, observational study was to analyze oral health in patients planned for HSCT. Patients ≥18 years requiring HSCT were included from five sites between 2011–2018. General health, oral findings and patient-reported symptoms were registered in 272 patients. Oral symptoms around disease onset were reported by 43 patients (15.9%) and 153 patients (58.8%) reported oral complications during previous chemotherapy. One third of patients experienced oral symptoms at the oral examination before conditioning regimen and HSCT. In total, 124 (46.1%) patients had dental caries, 63 (29.0%) had ≥one tooth with deep periodontal pockets, 147 (75.0%) had ≥one tooth with bleeding on probing. Apical periodontitis was observed in almost 1/4 and partially impacted teeth in 17 (6.3%) patients. Oral mucosal lesions were observed in 84 patients (30.9%). A total of 45 (17.4%) of 259 patients had at least one acute issue to be managed prior to HSCT. In conclusion, oral symptoms and manifestations of oral disease were prevalent in patients planned for HSCT. The extent of oral and acute dental diseases calls for general oral screening of patients pre-HSCT.

symptoms and manifestations of oral disease were prevalent in patients planned for HSCT. The extent of oral and acute dental diseases calls for general oral screening of patients pre-HSCT.
Amsterdam, Amsterdam, The Netherlands and Radboud University Medical Center, Nijmegen, The Netherlands.
Patients �18 years old, scheduled for a conditioning regimen followed by autologous or allogeneic HSCT, were included in the study. Enrollment started at the first center in March 2011 and proceeded at intervals until May 2018. Initially, patients who were planned for full intensity or reduced intensity conditioning treatments were eligible for inclusion. From November 2016, patients planned for non-myeloablative conditioning were also eligible for inclusion. Exclusion criterion included patients unable to give consent. The Orastem Study protocol has been presented in detail [23]. Briefly, the whole study design includes five study phases starting with a baseline assessment before HSCT (Table 1). In this first substudy, data from the baseline assessment (phases I and IIa) are reported.

Baseline pre-HSCT assessment
At the pre-HSCT assessment, scheduled 1-8 weeks before planned HSCT, age, gender, and anamnestic data on general health were collected. Data regarding current medication(s), medical diagnosis requiring HSCT, type of transplantation, previous radiotherapy to the head and neck, as well as previous and current bisphosphonate therapy were collected from medical records. Height and weight were recorded.
Patients were interviewed at baseline about experienced oral symptoms from around the time of onset of disease requiring HSCT and at previous chemotherapy treatments. Data Table 1. Orastem study design.

Phase Timepoint Assessments
Phase I 1-8 weeks before HSCT Baseline pre-HSCT assessment *general health *patient-reported early oral problems related to disease requiring transplantation *oral health-related habits Phase II a 1-8 weeks before HSCT Baseline pre-HSCT oral assessment *oral and dental status *patient-reported current oral problems b Shortly before HSCT Dental health assessment at HSCT *recent dental treatments (after oral examination before HSCT) *dental diseases left untreated *transplantation-related factors Phase III Early post-transplantation, 3  regarding oral health-related habits, i.e., routine or not routine (only for acute problems or never) dental care and oral hygiene habits (frequency of tooth brushing and cleaning between teeth), tobacco and alcohol use (never, previous, current, and extent), were collected. Patients were considered as previous smokers or previous alcohol users if they had ceased smoking or ceased using alcohol, respectively, more than four weeks ago. Baseline oral clinical assessment included a standard examination of oral hard and soft tissues, radiographic examination of teeth and surrounding tissues and registration of patientreported current oral problems.
Number of teeth, dental implants, teeth with root canal filling, teeth with caries into dentin or pulp or pulpal exposure (due to caries, fracture, or wear) as well as number of symptomatic teeth, partially impacted teeth, asymptomatic and symptomatic apical periodontitis (AP) were recorded. Level of periodontal disease was documented by number of teeth with probing pocket depth (PD) >5mm and bleeding on probing (BoP), registered on four tooth surfaces when possible, considering risk of bleeding and infection susceptibility. Presence of supra-and subgingival calculus was registered by clinical examination, probing and/or radiographic examination. Oral hygiene was measured by no presence or presence of plaque visible to the naked eye, moderate or abundant plaque accumulation corresponding to grade 2 or 3 plaque accumulation, respectively, as described by Silness & Löe [24]. Oral hygiene in the present study was considered excellent if no teeth had visible plaque, good if 1-20% of teeth had visible plaque and intermediate or poor if 21-50% or >50% of teeth had visible plaque, respectively.
Oral mucosal lesions were described based on location, clinical appearance, and diagnosis. Microbiological samples and/or biopsies were obtained when clinically necessary. Oral mucositis was measured using the World Health Organization (WHO) toxicity scale (score 0-4) [25]. Stimulated whole salivary (SWS) flow rate was measured using paraffin chewing for 5 minutes and reported as mL/min. Patient-reported current oral symptoms at the baseline pre-transplant oral assessment included symptoms from teeth, oral mucosa, and other oral problems. Subjective feeling of dry mouth (xerostomia) was graded with a numeric rating scale (NRS; 0-10).

Ethical considerations and validation of data
Approval from the Ethical Review Boards at each study site was obtained. Sweden: Regional Ethical Review Board in Gothenburg (513-10, T939-16); Charlotte: Wake Forest School of Medicine Institutional Review Board (IRB00080071); Vancouver: BC Cancer Agency Research Ethics Board (BCCA REB # H11-02350, BCCA REB # H15-02350); Amsterdam and Nijmegen: Medical Ethical Research Committee, Amsterdam University Medical Center location AMC (NL52117.018.15), registered in the Dutch Trial Register (NL 5645). The approval granted in Amsterdam was validated by the IRB of Radboud UMC in Nijmegen. Written informed consent to participate in the study was provided by all patients. All data were registered and encrypted in a database using the computer software-program MedView [26]. All data were validated in several steps to identify systematic errors.

Statistical analyses
Analyses for establishing oral health and oral symptoms at baseline are primarily descriptive in nature using frequency tables for categorical variables and summary statistics, such as median and range, for numerical variables. A comparison among enrollment sites with respect to stimulated salivary flow was made using the nonparametric Kruskal-Wallis test. Logistic regression models were utilized to investigate associations between medical diagnoses and patientreported oral symptoms and complications pre-HSCT. In logistic regression models, the effects of interest were tested with likelihood ratio tests. Fisher´s exact test was used for analysis of the effect of oral hygiene on presence of pre-HSCT oral mucosal lesions. Association between SWS flow rate and patient reported grading of xerostomia was measured using the Kendall´s τ B correlation. Because of the exploratory nature of this study, the reported p-values were not adjusted for multiplicity of tests, and a p-value less than or equal to a comparisonwise Type I error rate of α = 0.05 was considered statistically significant. Analyses were performed with R statistical software [27], version 4.0.3, and the SAS Enterprise Guide version 6.1 (SAS Institute Inc, Cary, North Carolina, USA).
A sample size was used to obtain an estimate of the prevalence of each individual oral complication within 0.06 of the true prevalence using a 95% confidence interval. Calculated sample sizes ranged from 62-254 patients [23]. Thus, the most conservative sample size of 254 patients was used. The total number of participants was higher, with the assumption that around 10% of inclusions would not proceed to HSCT.

Results
In total, 275 study participants went through the Orastem phase I pre-HSCT registration (median age 56.0 years, 42.2% females). A majority, 235 patients (85.5%), were assessed two weeks or more before planned HSCT, 10 patients (3.6%) were evaluated less than one week before. Of the 275 study participants, 272 also went through the phase IIa pre-HSCT oral examination. Altogether, 171 patients (62.9%) were scheduled for allogeneic and 101 (37.1%) for autologous transplantation. A flowchart of all Orastem Study phases is shown in Fig 1. Enrollment was done in accordance with clinical logistic procedures at each study center. In Vancouver, Amsterdam and Nijmegen, patients were enrolled consecutively during their enrollment periods. In Sweden and Charlotte, consecutive enrollment was not always possible for logistic reasons, as interruptions in inclusion during some time intervals occurred due to lack of personnel resources.

General health
Most frequent medical diagnoses requiring transplantation were multiple myeloma (MM) n = 80, acute myeloid leukemia (AML) n = 67 and lymphoma n = 42. Baseline demographics and clinical characteristics are described in detail per center in Table 2. Since only five patients were included at Karolinska University Hospital in Stockholm, due to hospital reorganization, the two Swedish sites in Stockholm and Gothenburg are presented together (Sweden) since the patients at both sites are treated in accordance with the national treatment guidelines.
As shown, half of the patients had never smoked, almost half were previous smokers, while very few reported current smoking. A large majority of current or previous smokers, (83.9%) had smoked �5 years, and over half had smoked �10 cigarettes/day. Among the current smokers, five patients smoked a pipe or cigar. Only four patients reported use of smokeless tobacco. Of the 117 patients reporting current use of alcohol (Table 2), only 13 reported daily consumption.

Patient-reported early oral symptoms
Patient-reported oral symptoms at disease onset. Altogether, 43 patients (15.9%) experienced oral symptoms around the time of onset of disease requiring transplantation, and before medical treatment started. Overall, there were differences among diseases requiring HSCT with respect to the probability of these early symptoms (p = 0.001). Oral symptoms at disease onset were reported by 83.3% of patients with severe aplastic anemia (SAA), by 20-25% of patients with acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) and less frequently among patients with other diagnoses (Table 3A).

Patient-reported oral symptoms from previous cancer chemotherapy
A vast majority of patients (n = 260, 94.9%) reported a medical history of previous treatment with cancer chemotherapy. Of these, over half (n = 153, 58.8%) reported experiences of oral symptoms in conjunction with the previous chemotherapy, with taste changes, dry mouth and oral mucositis being the most frequent (Table 3B). Transplant-requiring medical diagnosis Other diagnoses a 11 (4.0) had an impact on the probability of having an oral complication from earlier chemotherapy (p = 0.005) with ALL, AML, and lymphoma patients reporting the highest rates of oral complications (Table 3B).

Oral health-related habits
The majority of patients reported routinely seeing a dentist or dental hygienist (Table 4), as opposed to never doing so (n = 9) or only for acute problems (n = 56). Regarding oral hygiene    habits (Table 4), of the almost half who reported cleaning between teeth less than once per day, 62.8% (n = 81) did so less than once per week.

Acute oral problems requiring treatment prior to HSCT
Dental and oral findings that constituted acute issues that needed to be addressed before HSCT included any of the following: symptoms of a sensitive tooth, tooth ache/symptomatic tooth with or without periapical lesion, tooth fracture, swelling from an infected tooth or erupting wisdom tooth, diffuse pain or myalgia and findings such as teeth with pulpal exposure. A total of 45 (17.4%) of 259 patients had at least one acute issue to be managed prior to HSCT.

Oral mucosal findings
Clinical oral mucosal findings at baseline oral examination were observed in 84 (30.9%) patients. About one fourth of these patients presented with >1 lesion. The oral mucosal findings, presented based on diagnoses, results of diagnostic tests, clinical appearances and assessment of mucositis are shown in Table 6 with a categorization modified from Robledo-Sierra et al. [28]. There was not significant evidence that the proportion of patients with pre-HSCT oral mucosal lesions was different between levels of oral hygiene, good/excellent versus intermediate/poor, at this pre-HSCT examination (p = 0.456).

Patient-reported oral symptoms at baseline pre-HSCT oral assessment
Almost one third, 81 patients (30.3%), reported one or more current oral symptoms at the baseline pre-transplant oral assessment ( Table 7). The nature and distribution of any oral symptoms were followed up with specific questions regarding if the symptoms were from teeth, from oral mucosa, or if they were other oral symptoms.
Of the 81 patients reporting current oral symptoms at baseline, over half (n = 45, 55.6%) reported symptoms from teeth, of which sensitive teeth (n = 16) and tooth or filling fracture (n = 12) were most frequent. Regarding other patient-reported dental symptoms at baseline, see Table 7. Of the 81 patients who reported current oral symptoms, a number of patients had symptoms involving oral mucosa (n = 34, 42.0%), and other oral symptoms (n = 72, 88.9%), shown in detail in Table 7. Dry mouth (n = 46) was the most frequently reported oral symptom, followed by taste changes (n = 28). In the grading of a subjective feeling of dry mouth by NRS, Table 7. Patient-reported oral symptoms at baseline pre-hematopoietic stem cell transplantation (HSCT) assessment. Total  AML  ALL  LYM  CLL  MDS  CML  MPN  SAA  MM  Other   No. of patients  272  67  17  42  8  17  10  15  6  79  11 Overall no. of patients (%) reporting any oral symptoms at baseline which all patients were asked to do, more than twice as many (n = 104) reported oral dryness (>0) on the NRS, compared to the 46 who spontaneously reported dry mouth to the open question on oral symptoms. The 46 patients who had spontaneously reported dry mouth, had a mean NRS score of 4.5 (median 4). The patients that did not spontaneously report dry mouth to the open question but still reported NRS >0, had a lower mean NRS score of 3.0 (median 2). When analyzing the association between patients' reported xerostomia (NRS>0) and SWS flow rate, NRS tended to decrease as SWS flow rate increased (Kendall´s τ B correlation coefficient -0.16, p = 0.001).

Discussion
Our study showed that oral findings and symptoms were prevalent in patients planned for HSCT. Certain medical diagnoses (SAA, AML, ALL and MDS) had a higher frequency of reported oral symptoms around disease onset compared to others. Certain medical diagnoses (ALL, lymphoma and AML) also had the highest frequency of reported oral complications during previous chemotherapy. At baseline assessment, almost half of the patients had dental caries, nearly one third had deep periodontal pockets and the same amount had oral mucosal lesions while approximately one fourth had apical periodontitis. In total, 16% of patients reported that they had experienced oral symptoms around the time they became ill with the disease ultimately requiring transplantation. There are few comparable studies but, in a recently published study, Busjan et al. [29] reported that almost half of patients with newly diagnosed acute leukemia reported experiences of gum bleeding, swollen, painful, and/or sensitive gingiva during the last 12 months before diagnosis [29]. Watson et al. [30] reported that about 30% of patients with newly diagnosed acute leukemia, had clinical oral mucosal manifestations of their disease. The prevalence of patient-reported oral symptoms in the present study may be affected by measurement bias considering that patients were asked to recall the symptoms they had experienced around onset of disease. The lower overall prevalence of patient-reported oral symptoms in our study, compared to the studies by Busjan and Watson, may also be explained by the fact that more medical diagnoses requiring HSCT than acute leukemia were included. Patients with acute leukemia may frequently present with oral symptoms and manifestations, sometimes as initial manifestation of disease. In the present study, the most common patient-reported symptoms were bleeding from gingiva or oral mucosa, swollen gingiva and ulceration, which support findings reported by Busjan and Watson [29,30].
Patients with SAA had the highest probability of experiencing oral symptoms around onset of disease, followed by acute leukemia and MDS. However, it needs to be recognized that the number of patients with SAA was small. Few large studies have been published on oral manifestations in patients with SAA. However, in accordance with our findings, Brennan et al [31] concluded that oral soft tissue manifestations in patients with aplastic anemia were frequent. We found that oral symptoms around disease onset were less frequent among patients with lymphoma, MPN, CML and MM. Reports of early onset oral symptoms and manifestations in patients with these medical diagnoses are scarce. Our study suggests that the relationship between medical diagnoses, especially SAA, acute leukemia and MDS, and the likelihood of oral problems around disease onset deserves further investigation.
Almost 60% of patients in our cohort recalled experiences of oral symptoms from previous chemotherapy. This is a high proportion, but less than recently published by Garcia-Chias et al. [32] who reported approximately 90% of patients receiving cancer chemotherapy for a solid tumor or hematological cancer experiencing oral side effects. In our study, taste changes and dry mouth were the most frequent oral problems from earlier chemotherapy. Similar problems but in higher frequency have been reported by others [32,33]. The differences in prevalence may well be explained by the fact that our results are based on interviews with open questions on patients' experiences of earlier treatments. Therefore, the answers could be subject to measurement bias. Patients with acute leukemia and lymphoma had the highest probability of experiencing oral symptoms from previous chemotherapy. There is limited knowledge on how oral side effects are related to type of malignancy and chemotherapy regimens [34,35]. Patients at risk of side effects could gain from individualized information on expected complications and may have a larger need for supportive care after chemotherapy. Thus, our report on oral symptoms related to type of medical condition requiring transplantation and chemotherapy regimen adds important information that can be used in the clinical setting. Due to the small sample size of some of the medical diagnoses in our study, the results for each specific medical diagnosis need to be confirmed.
Dental diseases were prevalent in this cohort, which is in accordance with other studies in recent years [17,18,30,[36][37][38]. In our study, the overall incidence of periodontal diseases, measured clinically as PD >5 mm and BoP, was observed in almost 30% and 75% of patients, respectively. A limitation in the present study regarding data on periodontal disease is that not all patients could be assessed for periodontal status because blood cell counts did not permit invasive procedures. Therefore, it is possible that the level of periodontal disease at baseline could actually have been somewhat higher or lower than reported. To overcome these issues, one may use radiographic methods to estimate the level of periodontal disease (bone loss). However, this method also has limitations since it does not provide information on the actual level of gingival and periodontal inflammation.
One third of the patients had unsatisfactory (intermediate to poor) oral hygiene. Selfreported oral hygiene habits showed that the large majority of patients had regular tooth brushing habits, while cleaning between teeth on a regular basis was less frequent. Good oral hygiene have been reported to reduce the risk of complications such as infections and oral mucositis post-HSCT [39][40][41][42]. Therefore, providing professional dental cleaning and oral hygiene instruction for these patients is important. The pre-HSCT oral examination provides an excellent opportunity for the dental profession to provide individualized advice and instructions on oral hygiene practices. Dental disease and the need for dental treatment was seen in patients with a history of both regular and non-regular dental care. Therefore, attention to dental care needs is seen in all patients, regardless of dental care history.
Many patients reported being previous smokers at baseline, while few patients reported current smoking. Considering that more than 80% of "ever smokers" had smoked for many years, it cannot be ruled out that a number of patients may have quit smoking when diagnosed with the disease requiring transplantation. This may also be true regarding alcohol use.
The type of mucosal lesions found in one third of the patients at baseline were similar to findings by others [29,30,43]. However, most other publications largely concerned patients with acute leukemia. Since the baseline assessment was performed within weeks before planned transplantation, many lesions may be related to either the medical condition or treatment.
Dry mouth/xerostomia and taste changes were the most frequent oral problems reported by patients at baseline. The majority of patients had received previous chemotherapy at some timepoint, which may induce taste changes as well as xerostomia [35,44,45]. Interestingly, when patients graded their xerostomia on a numeric rating scale, more than twice as many patients reported xerostomia (NRS >0), compared to the ones that spontaneously reported xerostomia on an open question regarding oral problems. It is possible that the use of open questions, the heterogenicity of the medical diagnoses and the timing and range of prior chemotherapy had an influence on the prevalence levels of these symptoms. Our finding that xerostomia and taste changes are frequent oral symptoms in these patients is supported by earlier studies [32,33,35,44], although questions remain on the impact of these problems on the overall well-being.
The average SWS in our study was slightly higher compared to what Uutela et al. [37] and Mauramo et al. [46] reported in similar cohorts. The SWS flow rate in our study was measured at baseline oral examination, while Uutela et al and Mauramo et al both measured SWS flow rate after conditioning therapy and immediately before HSCT. SWS flow rate differed between the sites, which could be explained by differences in medical diagnoses, national treatment protocols regarding number and types of prescribed medications, as well as other unknown factors. The association between SWS flow rate and xerostomia, measured by NRS, indicates that NRS may be a complementary tool to evaluate effects of SWS flow rate in these patients.
There is no standard of care for dental treatment in patients planned for HSCT and a recently published study indicated that chronic oral foci of infection did not increase infectious complications during intensive chemotherapy in patients who underwent autologous HSCT [38]. However, a decision analysis suggested that treatment prior to chemotherapy/HSCT may prevent the additional deaths of 18 out of every 10,000 patients and may reduce systemic infections by approximately one-third [11]. The fact that a notable part of the patients in our study presented with dental and mucosal diseases and findings weeks before HSCT calls for further studies on the impact of different oral diseases in these patient categories.
In summary, dental disease, oral findings and symptoms were common in this cohort of patients planned for HSCT. Almost one fifth presented with at least one acute dental disease. Based on the extent of oral symptoms and dental diseases found in our study, there is a need for more research regarding risk of complications after HSCT, how to prevent and reduce these complications and, in the long term, the impact of these conditions on general outcomes. The extent of acute dental issues calls for general oral screening of patients pre-HSCT.